T-2 toxin induces thymic apoptosis in vivo in mice.
A single intraperitoneal injection of T-2 toxin (0.35, 1.75, or 3.5 mg/kg body wt) induced time- and dose-dependent thymic atrophy in young female BALB/c mice. T-2 toxin (1.75 mg/kg) induced maximal atrophy by day 3 with complete recovery by day 7. Flow cytometric analysis showed that the CD4(+)CD8(+) double positive thymocyte population decreased markedly. Histopathological examination of the thymus indicated that the pattern of cell death in the thymocytes had a characteristic apoptotic morphology with cell shrinkage and nuclear condensation. The in vivo effects of T-2 toxin included the induction of DNA fragmentation of approximately 200 base pairs in ladder form and cell death in thymocytes. Furthermore, flow cytometric analysis of PI-stained thymocytes from animals dosed with T-2 toxin revealed the formation of apoptotic cells. Of nine kinds of trichothecene mycotoxins tested, T-2 toxin appeared to be the most potent agent to induce apoptosis in the thymus. We sought insight into the mechanism of T-2 toxin-induced apoptosis in vivo. Administration of the protein synthesis inhibitor, CHX (15 mg/kg ip), 5 min after T-2 toxin (1.75 mg/kg ip) inhibited the induction of apoptosis in thymocytes, suggesting that the de novo protein synthesis was necessary. By using adrenalectomized mice and anti-TNF-alpha antibody-injected mice, it was shown that neither endogenous glucocorticoid nor TNF-alpha appeared to be involved in the apoptotic process. Taken together, these findings suggest that T-2 toxin-induced thymic atrophy is associated with cell death through a mechanism of apoptosis.
Islam
Z
Z
Faculty of Agriculture, Kagawa University, Miki-cho, Kita-gun, Kagawa, 761-0795, Japan.
Nagase
M
M
Yoshizawa
T
T
Yamauchi
K
K
Sakato
N
N
D000818:Animals; D000906:Antibodies / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects*; D001284:Atrophy; D016516:CD4-CD8 Ratio / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology*; D053938:DNA Fragmentation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D005938:Glucocorticoids / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron; D009183:Mycotoxins / Q000633:toxicity*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D013605:T-2 Toxin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013950:Thymus Gland / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; D005938:Glucocorticoids; D009183:Mycotoxins; D011500:Protein Synthesis Inhibitors; D014409:Tumor Necrosis Factor-alpha; D003513:Cycloheximide; D013605:T-2 Toxin